A Randomized, Double-blind, Placebo-controlled Trial of Intravenous Erythropoietin in Patients with ST-Segment Elevation Myocardial Infarction – Primary Results of the REVEAL Trial

Disclosures The REVEAL Trial was funded through a contract with the Intramural Research Program of the National Institute on Aging (HHS-N-260-2005-00010-C) Sunil V. Rao, MD Research funding: Portola Pharmaceuticals, Cordis Corporation, Ikaria Consultant: sanofi-aventis, BMS, AstraZeneca, Daiichi Sankyo-Lilly, Terumo USA This presentation discusses the unapproved and unlabeled use of epoetin alfa in patients with acute myocardial infarction

Background Despite advances in STEMI management, it remains a significant cause of morbidity, mortality, and disability Patients who survive STEMI are at risk for infarct expansion, LV remodeling, and heart failure Given the global burden of heart failure, therapies that limit infarct size and attenuate LV remodeling are needed Preclinical studies demonstrate that erythropoietin plays a cardioprotective role in models of myocardial ischemia and ischemia-reperfusion

Erythropoietin 165 amino acid glycoprotein Recombinant epoetin alfa is FDA-approved for treatment of anemia May have pleiotropic effects Receptors on endothelial cells, cardiomyocytes Prior data + Increased angiogenesis + Recruitment of endothelial progenitor cells + Decreased apoptosis

Study objectives Determine the safety and efficacy of intravenous epoetin alfa (EPO) at reducing infarct size in patients with acute STEMI who have undergone successful primary or rescue PCI This comparison was composed of two phases: Dose-escalation safety phase Efficacy phase using maximal tolerated EPO dose

Inclusion criteria Exclusion criteria Age ≥ 21 years Prior heart disease MI, EF < 50%, CABG, prior PCI in IRA Need for CABG Blood pressure Shock, SBP > 180 mm Hg or DBP > 110 mm Hg at time of drug admin Thrombotic events Hypercoagulable disorder, thromboembolic event, venous thrombosis Hx of stroke/TIA, seizures Contraindication to MRI or gadolinium contrast (e.g., GFR < 30 cc/min) Clinical indication or contraindication for EPO Pregnant or nursing Age ≥ 21 years Acute STEMI with TIMI 0 or 1 flow in a major epicardial coronary artery Revascularization within 8 hours of symptom onset Successful rescue/primary PCI ≥ TIMI 2 flow with residual lesion < 50% in IRA

Primary and Secondary endpoints STEMI Primary or rescue PCI TIMI 0-1 flow in IRA Successful PCI IV EPO Matching saline placebo Primary and Secondary endpoints - Randomize - Study drug within 4 hrs

Primary and secondary endpoints Primary endpoint Infarct size (% of LV) in the territory of the IRA 2-6 days after study drug administration Measured by contrast-enhanced cardiac magnetic resonance imaging (CMR) Secondary endpoints Infarct size at 12 ± 2 weeks Measures of LV remodeling (LVESVi, LVEDVi, LVMi, LVEF) at early and late timepoints Safety endpoints Death, recurrent MI, arterial thrombotic events (stent thrombosis), VTE, stroke/TIA

Sample size Sample size for Efficacy cohort 55 patients/arm provides > 80% power to detect a ≥ 20% difference in infarct size between EPO and placebo

STOP TRIAL Treatment schema Efficacycohort Efficacycohort Saline Placebo N = 55 15000 u EPO 1:1 Safety cohort 1 Saline Placebo N = 10 15000 u EPO N = 20 Efficacycohort Saline Placebo N = 55 30000 u EPO 1:1 Safety cohort 2 Saline Placebo N = 10 30000 u EPO N = 20 Safety cohort 3 Saline Placebo N = 10 60000 u EPO N = 20 STOP TRIAL Unacceptable Unacceptable Unacceptable Randomization stratified by age (< 70 y, ≥ 70 y) and infarct location (anterior vs. non-anterior) Qualitative safety review by DSMB after each safety cohort

Treatment schema: Efficacy phase Efficacy cohort Saline placebo n = 55 60000 u EPO 1:1 Enrollment continued until at least 110 patients completed the first MRI Two prespecified subgroups analyzed: Age (< 70 yrs, ≥ 70 yrs), Infarct location (anterior, non-anterior)

Principal Investigator Enrollment: Top 10 sites Site Principal Investigator New York Methodist Hospital John Heitner, MD The Ohio State University Medical Center Subha Raman, MD Mayo Clinic Greg Barsness, MD Duke University Medical Center Sunil V. Rao, MD Henry Ford Medical Center Adam Greenbaum, MD Stony Brook University Medical Center Luis Gruberg, MD Geisinger Medical Center James Blankenship, MD Washington Hospital Center Ron Waksman, MD Lynchburg General Hospital Thomas Nygaard, MD Wake Forest University Baptist Medical Center Sanjay Gandhi, MD

Results (1) – Patient flow 222 pts, 22 sites 189 with early CMR 24 pts in 15K cohort 27 in 30K cohort 138 in 60K Efficacy cohort 124 (89.9%) of Efficacy cohort With 12 week CMR

Results (2): Baseline characteristics Total Efficacy Cohort EPO n=123 Placebo n=99 n=68 n=70 Mean age, yrs 56.8 58.8 55.6 57.4 % ≥ 70 yrs 16.3 18.2 16.2 15.7 % Female 18.7 21.2 10.3 20.0 % Diabetes 11.4 25.3 8.8 24.3 % HTN 47.2 53.5 41.2 48.6 % Current smoker 38.8 42.4 40.3 45.7 % Anterior MI 27.6 27.3 29.4 27.1 % Killip class I 100 94.8 95.5

Results (3): Procedural characteristics Total Efficacy Cohort EPO n=123 Placebo n=99 n=68 n=70 % Primary PCI 89.4 82.8 94.1 78.6 % Rescue PCI 10.6 17.2 5.9 21.4 Times (min) Symptom onset to reperfusion 207.5 208.3 210.9 201.9 Reperfusion to study drug 176.3 183.0 172.4 175.5 Randomization to study drug 47.5 39.9 47.9 39.6

Results (4): Primary endpoint Mean (SE) infarct size at 2-6 days after study drug admin EPO Placebo 25 20 EPO vs. placebo 15.8% vs. 15.0%, P=NS P-value adjusted for age, infarct location, enrollment phase 15 Infarct Size (%LV) 10 5

Results (5): Secondary endpoints 2-6 d CMR 12-wk CMR EPO n=68 Placebo n=70 n=61 n=63 Infarct size, % LV 15.8 15.0 10.6 10.4 LVESVi, mL/m2 34.7 32.6 34.1 32.0 LVEDVi, mL/m2 65.6 63.4 70.0 66.6 LVMi, g/m2* 74.2 69.2 67.3 61.8 LVEF, % 48.2 48.9 52.5 52.0 *P < 0.05 in unadjusted analysis P-values adjusted for age, infarct location, and enrollment phase

Results (7): Prespecified subgroups Mean (SE) infarct size at 2–6 days by age group and MI location

Results (6): Clinical safety endpoints EPO n=125 Placebo n=97 P Death 0.8 0.72 Re-MI 1.6 0.35 Stent thrombosis 2.4 0.17 VTE - Stroke Death/MI/Stroke/ST 4.0 0.04 Death/MI/Stroke 3.2 0.08 Any AE 55.2 41.2 Any SAE 20.0 10.3 0.05 Values shown are percentages

Summary (1) Compared with placebo, a single intravenous bolus of 60,000 u of EPO in STEMI patients who have undergone successful primary or rescue PCI did not reduce infarct size at either the early or 12- week time points It did not favorably affect measures of LV remodeling at either the early or 12-week time points

Summary (2) EPO as studied in the REVEAL trial may increase infarct size among STEMI patients ≥ 70 years old Interpret with caution given the small number of patients ≥ 70 years old enrolled EPO was associated with a greater number of adverse clinical events compared with placebo

Conclusions These data, coupled with the lack of efficacy seen in other STEMI trials involving EPO (REVIVAL-31, HEBE III2), do not support the hypothesis that EPO favorably impacts outcome after reperfusion for STEMI Whether earlier administration or alternate dosing provides a cardioprotective effect of EPO in humans remains to be determined 1Ott I, et. al. Circ:CV Intv 2010 2Voors AA, et. al. EHJ 2010

REVEAL Trial Organization Principal investigator – Robert A. Harrington MD NIA Project Officer – Samer S. Najjar MD PhD Subinvestigators – Sunil V. Rao MD, Chiara Melloni MD MHS, Thomas J. Povsic MD PhD, Raymond J. Kim MD DCRI Project Lead – Laura Melton PhD Statistics – Kristi Prather MPH, Rakhi Kilaru MS, Vic Hasselblad PhD NIA – Mark Talan MD PhD, Luigi Ferrucci MD PhD, Dan L. Longo MD, Edward G. Lakatta MD DSMC – Lawrence J. Appel MD (chair), Victor Ferrari MD, Mark D. Kelemen MD, Jon R. Resar MD, Michael L Terrin MD, E. Pete Miller MD Thank you to all REVEAL Trial investigators, Study coordinators, and patients